Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with tumor progression and metastasis. The VEGF family of ligands (-A, -B, -C, -E, and PIGF) binds to three tyrosine kinase receptors (VEGFR-1, -2 and -3) that have been well characterized on endothelial cells. Initially, these receptors were identified on endothelial cells and were believed to be endothelial cell specific. In recent years, these receptors were noted on hematopoietic stem cells, monocytes, and osteoblasts and more recently on tumor cells. However, the function of these receptors on tumor cells remains to be elucidated. In preliminary studies, we found frequent expression of VEGFR-1 in human colorectal cancer (CRC) cell lines and surgical specimens. In addition, we found that VEGF ligands could activate downstream signaling pathways and increase migration and colony formation in CRC cells. These preliminary findings suggest that VEGFR-1 may play a role in tumor progression and thus may be a direct target for therapy, in addition to the effects of anti-VEGFR-1 therapy on tumor angiogenesis. The overall aim of this grant is to determine the functional role of VEGFR-1 on human CRC cells. Specifically we will: 1) Determine signaling pathways activated by VEGFR-1 in human CRC cells and determine their role in processes involved in tumor progression and metastasis 2) Determine the effect of inhibition of murine (host endothelial cell) and human (tumor cell) VEGFR-1 in a murine model of human CRC in nude mice 3) Determine the effect of inhibition of VEGFR activity on chemosensitivity of human CRC cells in vitro and in vivo. If VEGFR-1 mediates processes that lead to tumor progression and metastasis, therapeutic agents aimed at targeting VEGFR-1 may be of benefit to patients whose CRC tumors express VEGFR-1 (in addition to the antiangiogenic effect of these agents). In addition, it is possible that VEGFR-1 expression on CRC cells may serve as a "predictive factor" for anti-VEGF/receptor containing anti-neoplastic regimens.